Direct interaction between TDP-43 and Tau promotes their co-condensation, while suppressing Tau fibril formation and seeding

Abstract Neuronal aggregates of Tau are a hallmark of Alzheimer’s disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions, while some have co-aggregates of the two proteins. The presence of such co-aggregates is associated with increased disease severity, although whether there is a causal relationship remains unclear. Here, we demonstrate that Tau and TDP-43 mutually promote each other’s condensation through direct interaction in vitro, forming irregularly-shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau mobility. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with these data, insoluble material extracted from AD patient brains with Tau/TDP-43 co-aggregates exhibits reduced Tau seeding compared to AD patient brains with Tau aggregates only. In contrast, patient-derived extracts from AD patient brains with Tau/TDP-43 co-aggregates are highly potent in seeding new TDP-43 aggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction between TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology in Alzheimer’s disease patients.